Pain is an important biological defense mechanism which reflects the addition of any invasion to organisms. When pain or dysesthesia still lasts even after tissue damage or diseases responsible for the onset of pain have been cured, such a condition is recognized as a disease. Pain is broadly classified into nociceptive pain and neuropathic pain. Nociceptive pain includes pain caused by tissue inflammation, cancer-induced nerve compression, or the like (inflammatory pain, cancer pain, etc.). Non-steroidal anti-inflammatory drugs (NSAIDs) or opioids are therapeutically effective for the treatment of nociceptive pain.
On the other hand, neuropathic pain is chronic pain caused by nerve tissue damage or compression, or the like. Symptoms of neuropathic pain include unpleasant dysesthesia such as continuous or sudden spontaneous pain, numbness, burning sensation, the pain of being cut into small pieces, and stabbing pain; a condition which is a painful response to a usually non-painful weak stimulus (hyperalgesia); pain due to a stimulus that does not normally provoke pain (allodynia), such as caused by contact with clothing or changes in temperatures; and the like. Specific diseases of neuropathic pain include trigeminal neuralgia, complex regional pain syndrome, post spinal surgery syndrome, phantom limb pain, pain after brachial plexus injury, post-spinal cord injury pain, post-stroke pain, painful diabetic neuropathy, postherpetic neuralgia, HIV-induced neuropathy, and further some cases of cancer pain and low back pain on which analgesic effects of opioids are not sufficiently exerted, in addition to anticancer drug- and anti-HIV drug-induced neuropathy.
Neuropathic pain is known as pain on which NSAIDs or opioids which are effective on nociceptive pain exhibit difficulty in being therapeutically effective. In practical medication therapy, alleviation of pain is effected by hemp, capsaicin cream, or intraspinal administration of opioids, as well as by administration of antidepressants (duloxetine, amitriptylin, etc.), antiepileptic drugs (pregabalin, carbamazepine, etc.), or local analgesics (mexiletine, etc.). Unfortunately, effects of these drugs are limited since many neuropathic pains are developed by an overlap of multiple pathogenic causes and individual patients have different disease backgrounds. Further, there are also problems associated with inherent side effects of individual drugs. To this end, there is a strong need for an anti-neuropathic pain agent which has more potent and broader analgesic spectrum and lower side effects.
Irritable bowel syndrome (IBS) is a syndrome which brings about abdominal symptoms such as abdominal pain and abdominal distension and stool abnormalities such as diarrhea or defecation urgency and constipation or difficulty in defecation, due to the dysfunction of the lower digestive tract around the large intestine, despite no occurrence of organic alteration such as inflammation and tumor. Depending on predominant bowel habits, IBS is broadly subclassified into diarrhea type IBS (IBS-D), constipation type IBS (IBS-C), and mix type IBS (IBS-M) with alternating diarrhea and constipation (Gastroenterology 130: 1377-90, 1480-91 (2006)). As a medication therapy for IBS, there may be mentioned anticholinergic drugs for abdominal pain, tricyclic antidepressants (TCAs) for improving decreased pain threshold of the digestive tract, and in the case of bowel movement disturbance, antidiarrheals or intestinal remedies for diarrhea and cathartic salts for constipation, which are merely allopathic therapies and are also uncertain in their effects (Irritable bowel syndrome˜Communication between the brain and the intestines (ISBN4-521-67671-5, 2006)).
As drugs which are recently attracting attention, alosetron which is a 5-HT3 receptor antagonist and tegaserod which is a 5-HT4 receptor agonist are used for IBS-D and IBS-C, respectively. However, use of alosetron is limited due to the incidence of constipation in 30% to 35% of patients, in conjunction with serious side effects of ischemic colitis (including death), even though it exhibits a comparatively high improvement rate of 40% to 60% for abdominal symptoms and diarrhea (Drug Today 36: 595-607 (2000), FDA information about lotronex, GlaxoSmithKline press release). In addition, it is said that tegaserod has little effect on abdominal symptoms due to poor constipation-alleviating effects, which may result in the risk of tachyphylaxis (phenomenon of producing resistance to a drug after repeated doses over a short period of time) (Clinical Therapeutics 25: 1952-1974 (2003)). In addition, an application of tegaserod is also strongly limited in terms of side effects, due to having adverse effects on the circulatory system (FDA information about zelnorm, Novartis press release).
Opioids, such as morphine, which have been commonly used as pain-relieving drugs, are known to cause severe dysfunction of the digestive tract including constipation, which is called opioid bowel dysfunction (OBD). Among symptoms of OBD, the onset of constipation is very high without creating drug resistance unlike other opioid-induced central nervous system side-effects, so it is necessary to take appropriate measures to deal with the situation (American J. Surgery 182: 11S-18S (2001), Jpn. Cancer Chemother. 32: 1377-1383 (2005)). For these reasons, in opioid treatment particularly on cancer pain patients, a combined prophylactic treatment with a laxative agent is essential from the beginning of administering an opioid drug, but it is not easy to control defecation by means of the laxative agent (Drugs 63: 649-671 (2003), Pharmacotherapy 22: 240-250 (2002)).
The digestive tract is provided with an independent nerve network, called the enteric nervous system. Various kinds of neurons are present in the enteric nervous system and are responsible for governing respective digestive tract functions. Among those neurons, Intrinsic Primary Afferent Neutrons (IPANs) are neurons that primarily receive changes in the digestive tract lumen. IPANs detect physical or chemical changes in the digestive tract lumen and transmit the information to motor neurons or sensory neurons. Therefore, drugs altering the activity of IPANs bring about changes in the digestive tract function, called peristaltic motion or visceral perception (Progress in Neurobiol. 54: 1-18 (1998)). Further, from the fact that the N-type Ca2+ channel is expressed in IPANs and contributes to the activity of IPANs (J. Comp. Neurol. 409: 85-104 (1999)), it can be considered that a compound blocking the N-type Ca2+ channel would be useful for functional digestive tract diseases by altering digestive tract functions.
In addition, it is known that abdominal pain signals, like somatic pain, travel to the brain via the dorsal root ganglion (DRG) and the spinal cord (Neurogastroentel. Motil. 16: 113-124 (2004)). This signaling pathway is hypersensitized in IBS patients, suggesting significant occurrences of abdominal symptoms (Gut 53: 1465-1470 (2004)). Therefore, it is anticipated that a blocker of the N-type Ca2+ channel involved in this pain-signaling pathway would be an effective therapeutic agent against abdominal symptoms of IBS. In fact, it has been reported that gabapentin or pregabalin, which is a ligand for the Ca2+ channel α2δ subunit, exerts analgesic effects in animal models of abdominal pain hypersensitization (J. Pharmacol. Exp. Ther. 295: 162-167 (2000), Anesthesiology 98: 729-733 (2003)).
There are many kinds of Ca2+-dependent functional proteins in cells, and changes in the intracellular Ca2+ concentration play an important role in the expression or regulation of various physiological functions such as neuronal viability, synaptic plasticity, and gene expression. Among Ca2+ channels present on the cell membrane, a channel using a membrane potential as a trigger in the opening of the channel is called a voltage-dependent Ca2+ channel (VDCC), which consists mainly of an α1 subunit forming the channel body, a β subunit controlling an expression level of the α1 subunit or functions of the channel, and an α2δ subunit (Trends Neurosci. 21 148-154 (1998)). The Ca2+ channels are classified into high-threshold Ca2+ channels such as L-type (α1S, C, D, and F), P/Q-type (α1A), N-type (α1B), and R-type (α1E); and low-threshold Ca2+ channels such as T-type (α1G, H, I), depending on α1 subunit type and activation threshold potential (Rev. Physiol. Biochem. Pharmacol. 139: 33-87 (1999)).
Among the high-threshold Ca2+ channels, the P/Q-, N-, and R-type Ca2+ channels are present in neuron synaptic terminals and serve as a trigger of the neurotransmitter release. In particular, the N-type Ca2+ channel is highly expressed in the dorsal root ganglion (DRG) (J. Neurosci. 15: 4315-4327 (1995)) which is a collection of cell bodies of the sensory neurons or the spinal dorsal horn (J. Neurosci. 18: 6319-6330 (1998)) which is a synaptic projection region of sensory neurons. Further, the spinal dorsal horn of neuropathic pain model rats exhibited an increased expression of the N-type Ca2+ channel in synchronization with the progression of hyperalgesia (Exp. Brain Res. 147: 456-463 (2002)). From these facts, it is believed that the N-type Ca2+ channel plays a role as a trigger that transmits an excess of pain signals to the brain.
With recent observations showing that a selective N-type Ca2+ channel-blocking peptide, ω-conotoxin (ω-CTx) exhibits broad analgesic effects in animal models of nociceptive, inflammatory and neuropathic pain, respectively (J. Pharmacol. Exp. Ther. 279: 1243-1249 (1996), J. Pharmacol. Exp. Ther. 287: 232-237 (1998), J. Pharmacol. Exp. Ther. 269: 1117-1123 (1994)), and no neuropathic pain occurs in α1B-deficient mice (EMBO J. 20: 2349-2356 (2001)), it has been suggested that the N-type Ca2+ channel is deeply implicated in the pathogenesis of neuropathic pain. In fact, it has been reported that chronic spinal administration of ziconotide (ω-conotoxin MVIIA:ω-CTxMVIIA) by means of an implantable pump improves hyperalgesia and allodynia in morphine non-responsive neuropathic pain patients (Clin. J. Pain 13: 256-259 (1997)). Further, it has been demonstrated that gabapentin or pregabalin, frequently used as an anti-neuropathic pain agent, binds with a high affinity to the Ca2+ channel α2δ subunit to exert thereby analgesic effects (J. Pharm. Sci. 100: 471-486 (2006)). Based on the above-mentioned findings, the N-type Ca2+ channel blocker is expected to be an excellent therapeutic agent for pain, particularly neuropathic pain. Further, from the fact that the N-type Ca2+ channel is involved in hyperactivity of neurons, cellular death and the like, the N-type Ca2+ channel blocker is consequently expected to be useful for the prevention or treatment of conditions or diseases associated with activation of the N-type Ca2+ channel, in addition to the above-mentioned pain. Taken altogether, it is believed that a compound having the N-type Ca2+ channel-blocking action would be useful for various pains such as neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, central nervous system diseases such as anxiety, depression, epilepsy, cerebral stroke and restless legs syndrome, digestive system diseases such as abdominal pain and irritable bowel syndrome, and urinary system diseases such as overactive bladder and interstitial cystitis.
N-type Ca2+ channel-blocking compounds have been hitherto reported. For example, it has been described that the following benzazepine derivatives have an action of blocking N-type Ca2+ channels and are useful as an agent for preventing and/or treating cerebral infarction, transient cerebral ischemic attack, encephalomyelopathy after cardiac surgery, spinal cord vascular disorders, stress-induced hypertension, neurosis, epilepsy, asthma, frequent micturition, and ophthalmic diseases, or as anti-pain drugs (Patent Document 1).

(See the above-referenced document for symbols in the formula)
However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.
Further, it has been described that the following diarylalkene or diarylalkane derivatives have an action of blocking N-type Ca2+ channels and are useful for treating pain, brain infarction, cerebral disorders caused by acute ischemia after the onset of cerebral hemorrhage, Alzheimer's disease, AIDS-associated dementia, Parkinson's disease, progressive degenerative diseases of the brain, neurological disorders caused by head injury, bronchial asthma, unstable angina, irritable colon inflammatory diseases, and withdrawal symptoms of drug addiction (Patent Document 2).

(See the above-referenced document for symbols in the formula)
However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.
Further, it has been described that the following tricyclic heteroaromatic compounds have an action of blocking N-type Ca2+ channels and are useful as a medicament, particularly an analgesic agent (Patent Document 3).

(See the above-referenced document for symbols in the formula)
However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.
Further, it has been described that the following substituted piperazine compounds have an action of blocking N-type Ca2+ channels and are useful for treating cerebral stroke, pain, anxiety, depression, gastrointestinal disorders, genitourinary disturbance, cardiovascular disturbance, epilepsy, diabetes, and cancer (Patent Document 4).

(See the above-referenced document for symbols in the formula)
However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.
Further, it has been reported that the following azacyclo compounds are useful for treating or preventing diseases associated with a flow of sodium ions of the sensory neuron channel, for example, pain such as chronic and acute pain, hypersensitivity diseases such as bladder diseases and irritable bowel syndrome, and demyelinating diseases (Patent Document 5).

(See the above-referenced document for symbols in the formula)
However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.
Further, it has been reported that the following compounds have a farnesyl protein transferase inhibitory activity and are useful as an anticancer drug (Patent Document 6).

(See the above-referenced document for symbols in the formula)
However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention. In addition, there is no disclosure or suggestion of their effects on N-type Ca2+ channel-blocking action, pain including neuropathic pain, and digestive system diseases including irritable bowel syndrome.
Further, it has been reported that the following compounds have an anti-arrhythmic action (Non-Patent Document 1).

(See the above-referenced document for symbols in the formula)
However, an English Abstract attached to the above-referenced Document contains no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention. In addition, there is no disclosure or suggestion of their effects on N-type Ca2+ channel-blocking action, pain including neuropathic pain, and digestive system diseases including irritable bowel syndrome.
Further, it has been reported that the following compounds have an anti-arrhythmic action (Non-Patent Document 2).

(See the above-referenced document for symbols in the formula)
However, an English Abstract attached to the above-referenced Document contains no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention. In addition, there is no disclosure or suggestion of their effects on N-type Ca2+ channel-blocking action, pain including neuropathic pain, and digestive system diseases including irritable bowel syndrome.
Further, it has been reported that the following compounds have an action of blocking Ca2+ channels and are useful as a hypotensive agent and an anti-arrhythmic agent (Non-Patent Document 3).

(See the above-referenced document for symbols in the formula)
However, an English Abstract attached to the above-referenced Document contains no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention. In addition, there is no disclosure or suggestion of their effects on N-type Ca2+ channel-blocking action, pain including neuropathic pain, and digestive system diseases including irritable bowel syndrome.
Further, it has been reported that the following compounds have a Ca2+ channel-blocking action, a Na+ channel-blocking action and a calmodulin inhibitory activity and are possibly useful in neuroprotective therapy (Non-Patent Documents 4 and 5).

(See the above-referenced document for symbols in the formula)
However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.
Further, the following compounds have been reported as an Orexin-2 receptor antagonist (Non-Patent Document 6). Additionally, it has also been suggested that an Orexin-2 receptor is involved in the transmission of nociceptive stimuli.

(Me in the formula represents methyl)
However, there is no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.
As other references which disclose compounds having a tetrahydroisoquinoline skeleton, there are Patent Documents 7 to 9. However, these documents contain no specific disclosure of a 1-substituted tetrahydroisoquinoline compound which pertains to the present invention.    [Patent Document 1] JP-A-2002-363163    [Patent Document 2] Pamphlet of International Publication No. WO 03/018538    [Patent Document 3] Pamphlet of International Publication No. WO 2004/089950    [Patent Document 4] Pamphlet of International Publication No. WO 2005/021523    [Patent Document 5] Pamphlet of International Publication No. WO 2005/005392    [Patent Document 6] European Patent Application Laid-open Publication No. EP 0 696 593    [Patent Document 7] Pamphlet of International Publication No. WO 01/85693    [Patent Document 8] Pamphlet of International Publication No. WO 02/079189    [Patent Document 9] Pamphlet of International Publication No. WO 03/082828    [Non-Patent Document 1] Fudan University Journal of Medical Science, 1987, 14 (1), 15-20    [Non-Patent Document 2] Fudan University Journal of Medical Science, 1989, 16 (1), 71-74    [Non-Patent Document 3] Journal of China Pharmaceutical University, 1993, 24 (4), 193-201    [Non-Patent Document 4] Biological & Pharmaceutical Bulletin, 2000, 23 (3), 375-378    [Non-Patent Document 5] Neurochemical Research, 2003, 28 (12), 1813-1818    [Non-Patent Document 6] Bioorganic & Medicinal Chemistry Letters, 2003, 13 (24), 4497-4499